1. Field of the Invention
This invention relates to a process for preparation of cholecalciferol derivatives having a double bond in the side chain, particularly calcipotriol (calcipotriene).
2. Description of the Related Art
Calcipotriol, (1α,3β,5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol, is a synthetic vitamin D3 analogue. It exhibits antiproliferative activity and is useful in the treatment of psoriasis.
There are several known methods for the preparation of calcipotriol. The preparation method developed by Calverley (WO 87/00934; Tetrahedron 43, 4609 (1987)), is based on a Wittig reaction of C-22 aldehyde derivative of cholecalciferol, having a triene (5E,7E) configuration, with triphenylphosphorane cyclopropyl ketone glide. The reduction of the side chain carbonyl group to C-24 alcohol, gives a mixture of C-24 diastereomers. The disadvantage of this process is the formation of triphenylphosphine oxide as a side product which is water insoluble and difficult to remove from the reaction mixture. The desired (24S)-alcohol must separated by column chromatography, which leads to a loss of over a half of the obtained product. As a consequence, the undesired product, i.e., the (5E,24S) isomer, is subjected to photoisomerization to yield the product of a proper (5Z),(24S) configuration.
WO 2005/095336 employs the more reactive phosphonate derivative instead of triphenylphosphorane in a Wittig-Horner reaction. A phosphate ester formed in the reaction is soluble in water, unlike the triphenylphosphine oxide, and thus can be easily removed from the reaction mixture. Despite this improvement, the disadvantages of Calverley's synthetic pathway still remain and it is necessary to separate C-24 diastereomers in the last step.
Another method for preparing calcipotriol (Synlett, 1990, 157) relies on condensing C-22-seleneacetal with a fragment of the side chain, namely, (S)-2-((tert-butyl)dimethyl)silyloxy-2-cyclopropylacetyl aldehyde, resulting in the formation of a mixture of diastereoisomeric 23-hydroxy-22-methylselenides. These are treated with methanesulfoneyl chloride and triethylamine. In the two following steps, hydroxyl and selenemethyl groups are removed, resulting in the formation of a mixture of (5E),(22E/Z) olefins as their protected triols. The mixture is chromatographically separated and the obtained product of (5E),(22E) configuration is subjected to anthracene-sensitized photoisomerization of (5E,7E)-triene to (5Z,7E)-triene, followed by the removal of the silyl groups. On account of some drawbacks concerning work with seleneorganic compounds (unpleasant odor, toxicity and low stability of methylselenol), and lack of stereoselectivity during selenium removal from (α-hydroxy)methylselenides, this method is not suitable in a large scale production.
Another way of obtaining calcipotriol, accompanied by its C-24 epimer, is disclosed in JP 08325226. This method is based on coupling of two synthons: calcipotriol A ring -(4R,6S)-4,6-di(t-butyl)dimethylsilyloxy-7-octen-1-yne and a 7-bromo derivative consisting of calcipotriol CD rings, under Heck reaction conditions. The coupling is followed by removal of protecting groups. The synthesis of both synthons used in the coupling-cyclization reaction proved to be a difficult multistep process.
In JP 06316558 disclosed is the preparation of (7Z)-calcipotriol isomer from appropriately substituted cholesta-5,7-diene in a photochemical or thermal rearrangement process.
The prior art methods for the preparation of calcipotriol have certain disadvantages connected with easy isomerization of the asymmetric center at C-20 of the starting C-22 aldehydes, lack of selectivity during C-24 ketone reduction and the necessity for use of preparative chromatography during purification step. These factors adversely affect the implementation of the described syntheses in routine laboratory practice.
A number of methods were developed to increase the total yield of calcipotriol synthesis, whereas undesired (24R)-isomer is transformed into the mixture enriched with the desired (24S) epimer. In WO 03/106412, the method of regaining the desired calcipotriol (24S) epimer is disclosed. The process is based on the racemization of calcipotriol C-24 p-nitrobenzoate under Mitsunobu reaction conditions using diisopropyl azadicarboxylate.
In WO 2006/024296 in turn, the epimerization of C-24 alcohol in aqueous organic medium under acidic conditions is disclosed. In this process no additional hydroxyl group transformation is necessary. Although this procedure is superior to the one described in WO 03/106412 as the esterification as well as alcohol hydrolysis are avoided, the problems with diastereomer separation and with the inability to isolate over half of the obtained racemic mixture still exist.
Some attempts were undertaken towards calcipotriol preparation in direct olefination method under Julia-Kocienski protocol, known in the art (P. R. Blakemore at al., Synlett, 26 (1998); P. R. Blakemore at al., J. Chem. Soc., Perkin Trans. I, 955 (1999)), applying a phenyltetrazole sulfone. This method was applied in the synthesis of cholecalciferol derivatives (Kutner, A., Przem. Chem., 85(5), 322 (2006)). The attempts to overcome the difficulties with low transformation rate of thiophenyltetrazole derivative into appropriate sulfoneylphenyltetrazole have failed. In addition, the high cost of commercially available main reagent, 1-phenyltetrazole-5-thiol, may be limiting in the implementation of this method in the production scale.
In WO 03/087048 disclosed is a method of calcipotriol preparation using benzothiazole sulfone. Use of benzothiazole sulfone was first reported for the direct aldehydes olefination by Sylvestre Julia (J. B. Baudin at al., Tetrahedron Lett. 32, 1175 (1991)). In the Julia olefination, condensation of deprotonated benzothiazole sulfone and aldehyde under basic conditions proceeds, followed by subsequent cyclization and rearrangement, accompanied by sulfur dioxide elimination. As a reaction result, olefin is formed as well as a water soluble benzothiazolone salt (J. B. Baudin at al., Bull. Soc. Chim. Fr. 130, 336 (1993); Bull. Soc. Chim. Fr. 130, 856 (19930).
Oxidation of benzothiazole sulfide to sulfone, unlike phenyltetrazole sulfide, proceeds in moderate yield (62%). Crystalline C-22 sulfonyl benzothiazole derivative is a convenient, advanced intermediate in the synthesis of calcipotriol. However, under the reaction conditions with the use of benzothiazole sulfone, (22Z) by-product is formed in over 10% yield. The removal of this by-product up to the pharmaceutically accepted level is accomplished in a multi-step crystallization process. The elaborate purification procedure affects the total yield of the synthetic process.
In the art, Marc Julia's (M. Julia, J. M. Paris, Tetrahedron Lett. 1973, 4833) olefination method was one of most frequently used, when C═C double bond formation in a molecule was necessary. In this process aldehyde reacted with phenyl sulfonyl anion, generated in situ when treated with n-butyl lithium; obtained intermediate was subsequently functionalized and subject to reductive elimination with sodium amalgam to yield alkene.
Regardless of the popularity of this method, it has not been applied in direct condensation of cholecalciferol C-22 phenylsulfonyl derivative, having methyl group at the alfa position in respect to the phenylsulfonyl substituent, and aliphatic aldehyde having at alfa position bulky substituent, such as tert-butyl-diphenylsilyl. In light of WO 03/087048, that type of hydroxyl protection facilitates purification and isolation of the reaction product. The silyl protection also enables the starting aldehyde detection by UV spectroscopy in TLC and HPLC chromatography, and causes the increase of molecular density and decrease of volatility thereof.